Use of allopurinol for the treatment of hand foot skin reaction

ABSTRACT

Use of allopurinol or a pharmaceutically acceptable salt thereof for the treatment or prevention of Hand Foot Skin Reaction (HFSR) induced by Multitargeted Kinase Inhibitor (MKI) therapy. The allopurinol or its salt is administered topically to the affected areas, palms and soles, preferably in the form of a cream.

This application claims benefit of U.S. Provisional Application No.61/214,894, filed Apr. 29, 2009 and claims priority of European PatentApplication No. EP 09 382 058.7, filed Apr. 29, 2009, and. The contentsof all of the referenced applications are hereby incorporated byreference into the present application.

FIELD OF THE INVENTION

The present invention relates to the field of therapy, especially inoncology. It relates to the use of allopurinol or its pharmaceuticallyacceptable salts for the treatment or prevention of Hand-Foot SkinReaction (HFSR) induced by Multitargeted Kinase Inhibitors (MKI). Italso relates to methods for the treatment of HFSR.

BACKGROUND OF THE INVENTION

Cancer is a group of diseases in which abnormal cells divide withoutcontrol. Cancer cells can invade nearby tissues and can spread throughthe bloodstream and lymphatic system to other parts of the body. Thereare several main types of cancer. Carcinoma is cancer that begins in theskin or in tissues that line or cover internal organs. Sarcoma is cancerthat begins in bone, cartilage, fat, muscle, blood vessels, or otherconnective or supportive tissue. Leukemia is cancer that starts inblood-forming tissue such as the bone marrow, and causes large numbersof abnormal blood cells to be produced and enter the bloodstream.Lymphoma and multiple myeloma are cancers that begin in the cells of theimmune system.

Several treatments are available for cancer, including surgery andradiation for localised disease, and drugs that destroy cancer cells(chemotherapy). Chemotherapy plays a significant part in cancertreatment, as it is required for the treatment of advanced cancers withdistant metastasis and often helpful for tumour reduction before surgery(neoadjuvant therapy). It is also used following surgery or radiation(adjuvant therapy) to destroy any remaining cancer cells or preventrecurrence of the cancer.

Many anti-cancer drugs have been developed based on various modes ofaction: alkylating agents that act directly on the DNA (such ascisplatin, carboplatin, oxaliplatin, busulfan, chlorambucil,cyclophosphamide, ifosfamide, dacarbazine); antimetabolites thatinterfere with DNA and RNA synthesis (such as 5-fluorouracil,capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine(ara-C), fludarabine); anthracyclines that interfere with enzymesinvolved in DNA replication (such as daunorubicin, doxorubicin,epirubicin, idarubicin, mitoxantrone); microtubule disrupters (taxanessuch as paclitaxel and docetaxel or Vinca alkaloids such as vinblastine,vincristine, and vinorelbine); topoisomerase inhibitors (such asetoposide, doxorubicin, topotecan and irinotecan); hormone therapy (suchas tamoxifen, flutamide) and recently introduced targeted therapy (suchas the inhibitors of EGFR cetuximab, gefitinib or the protein tyrosinekinase inhibitor imatinib), are the most frequently used.

The development of chemotherapy in the last decades has significantlyimproved the treatment of cancer, resulting in effective treatments insome types of cancers, and improved survival or time to progression inothers. Currently, most chemotherapy is administered intravenously;however, oral chemotherapy drugs are gaining wider use.

Unfortunately, most chemotherapy drugs cannot differentiate between acancer cell and a healthy cell. Therefore, chemotherapy often affectsthe body's normal tissues and organs which results in complication oftreatments, or side effects. In addition to the problems they cause,side effects can prevent doctors from delivering the prescribed dose ofchemotherapy, reducing the probability of a correct treatment of cancer.Most frequent side effects of chemotherapy are anaemia, neutropaenia,thrombocytopaenia, fatigue, alopecia, nausea and vomiting, mucositis andpain.

One the side effects associated with some chemotherapeutic agents,especially with 5-fluorouracil and its prodrug capecitabine, isPalmar-Plantar Erythrodysesthesia (PPE), an erythematous eruption of thepalms and soles also known as Hand Foot Syndrome (HFS). PPE is adistinctive and relatively frequent toxic reaction. It is a painfulswelling and erythematous rash, located in the palms and soles, oftenpreceded by dysesthesia, usually in the form of a tingling sensation,and often associated with oedema. The rash may become bollous and thendesquamate without scarring, and pain gradually increases. Erythema mayalso occur in periungal areas. Generally it is confined to the hands andfeet, the hands are usually more severely affected than the feet.

Histologically PPE shows mild spongiosis, scattered necrotic anddyskeratotic keratynocites and vacuolar degeneration of the basal layer.Dermal changes in most cases include dilated blood vessels, papillaryedema, and a sparse superficial perivascular limphohistiocyticinfiltrate that can be found in varying degrees in the epidermis.

PPE is clearly distinct from other adverse skin reactions and isreviewed in Nagore E. et al, Am J Dermatol. 2000, 1(4), 225-234. Despiteits frequency, little is known of its causes.

The advent of molecularly targeted therapies has changed the face ofcancer treatment in the last few years. Among the targeted therapies forcancer, there has been a keen interest in developing agents thatinterfere with angiogenesis, the process by which new blood vessels areformed. By blocking the activity of receptors such as the plateletderived growth factor (PDGFR) or the vascular endothelial growth factorreceptor (VEGFR), or by inhibiting members of their signalling pathways,tumour vessel formation can be halted and even reversed. Some of thesetargets are the ubiquitous mitogen-activated protein kinase (MAPK)pathway or Raf/MEK/ERK pathway, which controls the growth and survivalof human tumours in proangiogenic pathways, which also involvesignalling through MAPK. Solid tumours frequently exhibit activatingoncogenic mutations in ras and/or overactivation of Raf-1 kinase,resulting in dysregulated signaling through the MAPK pathway, andconsequent tumor cell proliferation and angiogenesis.

This rational approach to cancer treatment lead to the development of asecond generation tyrosine kinase inhibitors that are able to targetmore that one target and pathways. Agents targeting multiple pathways intumour growth are highly attractive, potentially offering the benefitsof combined therapy within a single agent. The majority of these neweragents inhibit more than one receptor tyrosine kinase and may haveunique inhibition profiles. Among the multitargeted kinase inhibitors(MKI's), sorafenib and sunitinib are already authorised for use, andvandetanib, motesanib, ABT-869 and several other compounds are stillunder development.

Sorafenib (Nexavar®) is an oral drug capable of inhibiting severalreceptor tyrosine kinases that are involved in tumour progression andangiogenesis. Sorafenib blocks Raf gene products (serine-threoninekinases), including mutated B-Raf, as well as platelet-derived growthfactor-beta (PDGFR-β), FLt3, and vascular endothelial growth factorreceptor-2 and -3 (VEGFR-2 and -3). Sorafenib has been approved by theFDA in 2005 and by the EMEA in 2006 for the treatment of metastaticrenal cell carcinoma and advanced hepatocellular carcinoma.

Sunitinib (Sutent®) is also an oral drug, a multitargeted tyrosinekinase inhibitor that blocks VEGFR-1, -2. and -3, PDGFR-α and -β, Ret,c-Kit, and FLT₃. In 2006 it has been approved by the FDA and by the EMEAfor use in patients with gastrointestinal stromal tumor (GIST) who arerefractory to or intolerant of imatinib mesylate, and in patients withmetastatic renal cell carcinoma. It is usually administered in a 4week-on, 2 week-off schedule, to allow patients to recover from somepotential toxicities.

The MKI's such as sorafenib and sunitinib have side effects, the mostfrequent being fatigue, hypertension, nausea and diarrhea. Their safetyprofiles are however generally more favorable than those of manystandard chemotherapies.

However, as with other tyrosine kinase inhibitors, MKI's are associatedwith significant dermatologic adverse reactions. Hand-Foot Skin Reaction(HFSR) is the most clinically significant (Rosenbaum S E et al. SupportCare Cancer (2008) 16:557-566 “Dermatological reactions to themultitargeted tyrosine kinase inhibitor sunitinib”; Robert C et al J AmAced Dermatol 2009, vol. 60 no. 2, 299-305 “Dermatological symptomsassociated with the multikinase inhibitor sorafenib”).

Hand-Foot Skin Reaction (HFSR) is a distinct localized cutaneousreaction characterized by erythema, numbness, tingling and eitherdysesthesia or paresthesia, particularly on the palms and or soles.Histologically, it is characterized by thick, well definedhyperkeratotic lesions frequently affecting digital flexural location.It develops within the first 2-4 weeks of MKI administration. Afterseveral weeks the lesions, with or without blisters, are followed byareas of thickened or hyperkeratotic skin resembling skin calluses thatare painful.

HFSR is described in: Lacouture M E et al. The Oncologist 2008, 13, no.9, 1001-1011: “Evolving Strategies for the management of Hand-Foot SkinReaction associated with the Multitargeted Kinase Inhibitors Sorafeniband Sunitinib”; Beldner M et al The Oncologist 2007 12:1178-1182“Localized Palmar-Plantar epidermal hyperplasia: a previously undefineddermatological toxicity to sorafenib”; Yang C H et al. British journalof Dermatology 2008, 158 592-596 “Hand-Foot skin reaction in patientstreated with sorafenib: a clinopathological study of cutaneousmanifestations due to multitargeted kinase inhibitor therapy”; Porta Cet al. Clin Exp Med 2007, 7:12-134 “Uncovering Pandora's vase: thegrowing problem of new toxicities from novel anticancer agents. The caseof sorafenib and sunitinib”; Wood L. et al. Community Oncology 2010,vol. 7, no. 1 opages 23-29: “Practical Considerations in the Treatmentof Hand Foot Skin Reaction caused by Multikinase Inhibitors”.

As explained in these publications, Hand-Foot Skin Reaction isdistinguished clinically and histologically from palmar plantarerythrodysestesia (PPE) [also known as Hand-foot syndrome (HFS)],induced by chemotherapy such as 5-FU, capecitabine, or pegylatedliposomal doxorubicine.

Both conditions show palmar-plantar localization, tenderness, pain andresolution of the toxicity upon discontinuation of the drug.

However, the typical pattern of localized hyperkeratotic lesionssurrounded by erythematous areas distinguishes HFSR from PPE, in whichsymmetric paresthesias, diffusely tender erythema and oedema occur.Further, HFSR can affect non pressure-bearing areas, such as toes andfinger webs, and the lateral sides of the soles. Pathologically, MKI'sinduce keratinocyte vacuolar degeneration in the stratum malpighiitogether with epidermal acanthosis, while PPE induced by chemotherapyshows dermal-epidermal interface dermatitis and vacuolar degeneration ofbasilar keratynocytes. The main histologic changes observed in HFSRsuggest a defect in cell maturation, with modifications in keratinocytedifferentiation, possibly increased apoptosis of this same cellpopulation, as well as a specific inflammation. The rate of epidermalcell replication is markedly accelerated in active lesions of HFSR. Themost relevant histopathological characteristic of HFSR is keratinocytedamage, present as intracytoplasmic eosinophilic bodies, unique to thiscondition. The mechanism by which HFSR originates is not known.

The incidence of HFSR is high. A meta-analysis has shown that thesummary incidence of HFSR in patients treated with sorafenib was 33.8%for grades 1-3, and 8.9% for grade 3 (Chu D., Lacouture M E et al. ActaOncologica 2008; 4 16-186: “Risk of Hand Foot Skin Reaction withSorafenib: A systematic Review and Meta-Analysis”). With sunitinib, thesummary incidence was calculated at 18.9% for grades 1-3 and 5.5% forgrade 3 (Chu D. Lacouture M E, et al. Clinical Genitourinary Cancer2009, no. 1 11-19: “Risk of Hand Foot Skin Reaction with theMultitargeted Kinase Inhibitor Sunitinib in patients with Renal Cell andNon-Renal Cell carcinoma: a Meta-analysis”). HFSR can negatively affecthealth-related quality of life and activities of daily living inpatients being treated with MKI's such as sorafenib and sunitinib.

The severity of HFSR is most widely done using the National CancerInstitute Common Terminology Criteria for Adverse Events (NCI-CTCAE v3.0). The clinical characteristics of each grade are:

-   1. Minimal skin changes or dermatitis (e.g. erythema) without pain-   2. Skin changes (e.g. peeling, blisters, bleeding, oedema) or pain;    no interference with patient activities of daily living;-   3. Ulcerative dermatitis or skin changes with pain; interferes with    patients activities of daily living.

It can also be graded using modified criteria which better fit withclinical practice (Porta C et al. Clin Exp Med 2007, 7:12-134):

-   -   1. numbness, dysaesthesia, paraesthesia, tingling, painless        swelling, erythema or discomfort of hands or feet, which does        not disrupt patient's normal activities;    -   2. One or more of the following symptoms: painful erythema,        swelling, hyperkeratosis of the hands or feet, discomfort        affecting the patient's normal activities;    -   3. One or more of the following symptoms: moist desquamation,        ulceration, blistering, hyperkeratosis, severe pain of the hands        and feet, severe discomfort that causes the patient to he unable        to work or perform daily activities.

There is at the moment no effective treatment for HFSR. Before treatmentwith MKI, removal of pre-existing hyperkeratotic areas and calluses isrecommended. Once the skin reaction appears after initiating thetreatment with MKI's, some of the few treatments that have been proposedare: cold compresses or ice packs, avoiding pressure on hands or feet;skin hydration; emollient skin creams, clobetasol ointment or topicalanalgesics. For the more severe grades (2-3), dose reduction orinterruption of the treatment with MKI's is recommended. Urea,fluorouracil and tazarotene creams have also been mentioned, since theseagents inhibit keratinocyte proliferation (Lacouture M E et al. TheOncologist 2008, vol. 13, no. 9, 1001-1011: “Evolving Strategies for themanagement of Hand-Foot Skin Reaction associated with the MultitargetedKinase Inhibitors Sorafenib and Sunitinib”, Anderson et al. TheOncologist 2009, vol. 14, no. 3, 291-302: “Search for evidence-basedapproaches for the prevention and palliation of Hand-foot Skin Reaction(HFSR) caused by the Multikinase Inhibitors”); Wood L. et al. CommunityOncology 2010, vol. 7, no. 1 opages 23-29 “Practical Considerations inthe Treatment of Hand Foot Skin Reaction caused by MultikinaseInhibitors”).

None of the proposed treatments has yet been able to effectively treator prevent HFSR. This is a serious problem for the patient, becausebesides the intrinsic discomfort and pain, in advanced grades it impliesin a reduction or interruption of the chemotherapy with MKI's, whichaffects the survival and/or time to progression of the cancer beingtreated. It is clear that an effective treatment of HFSR is stillneeded, in order to untie the full potential of multikinase inhibitorsand the different regimens and combinations in which they are and willbe used.

Allopurinol is a structural isomer of hypoxanthine, it inhibits xanthineoxidase, an enzyme that converts oxypurines to uric acid. By blockingthe production of uric acid, this agent decreases serum and urineconcentrations of uric acid, thereby providing protection against uricacid-mediated end organ damage in conditions associated with excessiveproduction of uric acid. It has been used for many years for thetreatment or prevention of gout, hyperuricemia and kidney stones,through oral or parenteral systemic administration.

Allopurinol has also been reported for the treatment of mucositis, afrequent chemotherapy- or radiation-induced damage to the rapidlydividing cells lining the mouth, throat and gastrointestinal (GI) tract.Allopurinol is used in the form of mouthwashes (dispersion in water)(Porta C. et al, Am J clin Oncol. 1994, Vol 17, no.3, 246-247). Animproved formulation for mouthwashes comprising allopurinol,carboxymethylcellulose and water is described in JP-3106817. Hanawa etal. in Drug Dev Ind Pharm 2004, 30(2) 151-161 describe another mouthwashcomprising allopurinol, polyethyleneoxide and carrageenan. Kitagawa etal. in J Radiation Research 2008, vol. 49, no. 1, 49-54, describe thatAllopurinol gel mitigates radiation-induced mucositis and dermatitis inrats. Dagher et al., Canadian Journal of Hospital Pharmacy, vol. 40,no.5 1987, page 189, discloses the use of allopurinol mouthwash andvaginal 0.1% cream for the treatment of 5-FU induced mucositis.

WO94/05293 and WO94/05291 describe synergistic compositions comprisingmethylsuphonylmethane (MSM) and at least one of oxypurinol orallopurinol and their use for the treatment of skin conditions, diseasesand injuries such as burns, dermatitis, hyperkeratosis, sun exposure,skin ageing, etc. Oxypurinol and allopurinol are described as enhancingthe skin healing or repairing properties of MSM.

WO2007/138103 discloses and exemplifies the use of allopurinol, inparticular topically in the form of a cream for the treatment of PalmarPlantar Erythrodysesthesia or Hand-Foot syndrome induced byfluoropyrimidine chemotherapy (5-FU and capecitabine). However, theskilled person knows that fluoropyrimidine and Multitargeted kinaseinhibitors act at a molecular level by a very different mechanism, andtheir skin toxicities are different, both clinically and histologically,as discussed above.

Indeed, a interdisciplinary panel of experts in Wood et al. (CommunityOncology) state at page 1 that:

“MKI-associated HFSR is a clinically and pathologically distinct skintoxicity from the HFS seen with older chemotherapeutic agents.”

None of the cited documents mentions or suggests that allopurinol wouldbe useful for the treatment or prevention of Hand-Foot Skin Reaction(HFSR).

SUMMARY OF THE INVENTION

The inventor has surprisingly found that allopurinol, when appliedtopically, in particular to the palms and soles of the patient, is veryeffective in the treatment and prevention of Hand Foot Skin Reaction(HFSR) induced by multitargeted kinase inhibitors (MKI). As show in theexamples, topical application of allopurinol to cancer patients, beingtreated with MKI's and having developed this condition, completelyeliminated the symptoms and avoided the further appearance of HFSR. Thisis more striking in the case of patients having developed the typicalhyperkeratosis of HFSR, since it would be expected to be very difficultto topically treat the thick corneal layer present in the palms andsoles, and also to reverse the process and bring the skin to a normalcondition in a short period of time, with the disappearance of thehyperkeratosis, as shown in one of the examples.

Therefore, in one aspect the invention is directed to a medicamentcomprising allopurinol or a pharmaceutically acceptable salt thereof foruse in the treatment or prevention of Hand Foot Skin Reaction induced bya multitargeted kinase inhibitor (MKI).

In a second aspect, the invention is directed to the use of allopurinolor a pharmaceutically acceptable salt thereof in the manufacture of amedicament in the treatment or prevention of Hand Foot Skin Reactioninduced by a multitargeted kinase inhibitor.

In a third aspect, the invention is directed to a method for treating orpreventing Hand Foot Skin Reaction induced by a multitargeted kinaseinhibitor in a patient affected or likely to be affected by thiscondition, comprising topically applying a therapeutically effectiveamount of allopurinol or a pharmaceutically acceptable salt thereof.

Further embodiments of the invention are defined in the claims.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “multi-targeted receptor tyrosine kinaseinhibitor” refers to a compound having a receptor binding profileexhibiting selectivity for multiple receptors shown to be important inangiogenesis.

In the context of the present invention, the term “Hand Foot SkinReaction” (HFSR) defines the side effect to the skin of hands and feetof a cancer patient being treated with a multi-targeted receptortyrosine kinase inhibitor. Their clinical and histologicalcharacteristics, and its grading are described above. As explained, itis different from Palmar-Plantar erythrodysesthesia (PPE), also known asHand-Foot Syndrome (HFS), induced by other chemotherapeutic agents suchas 5-FU and Capecitabine.

-   In the context of the present invention the term allopurinol refers    also to the different tautomers of the compound, since it is a    tautomeric mixture of 1H-pyrazolo[3,4-d] pyrimidin-4-ol and    1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one:

-   As mentioned above, the topical application of allopurinol or one of    its pharmaceutically acceptable salts has surprisingly been found to    be useful for the treatment and prevention of HFSR induced by MKI.

Thus, in one aspect the invention is directed to use of allopurinol or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment or prevention of HFSR induced byMultitargeted Kinase Inhibitor therapy.

In one embodiment the medicament is in the form of a cream. Preferablythe cream is a hydrophilic cream.

In another embodiment the medicament is for the treatment of HFSRinduced by the MKI sorafenib, either alone or in combination with otheragents.

In another embodiment the medicament is for the treatment of HFSRinduced by the MKI sunitinib, either alone or in combination with otheragents.

The medicament thus useful for the treatment of patients suffering fromcancer, preferably from renal cell carcinoma, hepatocellular carcinoma,breast cancer, gastrointestinal stromal tumors (GIST), non-small celllung cancer (NSCLC), melanoma, and that are receiving MKI therapy,either as adjuvant, neoadjuvant or palliative. Examples of patients andtherapies inducing HFSR have been discussed in the section “backgroundof the invention”.

The medicament containing Allopurinol for the treatment of HFSR isparticularly useful in patients receiving or about to receive sorafenib,sunitinib, or other MKI's, either alone or in combination with otheragents.

Local application of allopurinol allows an effective targeting of theaffected areas, and avoids the toxicities and complications thatsystemic allopurinol can provoke in cancer patients. It avoidsinterfering with the cancer therapy.

Allopurinol is a compound very slightly soluble in water and alcohol;practically insoluble in chloroform and in ether; it dissolves in dilutesolutions of alkali hydroxides. It can be used as such, or, to improvethe solubility in water, a salt such as the sodium salt can be usedinstead of the base.

In a preferred embodiment, the medicament is in the form of a topicalpharmaceutical composition for the treatment of the hands and feet,comprising allopurinol or a pharmaceutically acceptable salt thereof,together with at least one topically acceptable carrier material.

In the topical compositions used to treat HFSR, allopurinol or its saltis typically present in an amount of from about 1 up to 10%, inparticular from 1-8%, more particularly from 1-6%, especially from 1 upto 5%. Concentrations of about 1%, about 3% and about 8% are preferred.

A preferred range is from 2 up to 5%, more preferably from 2-4% of thetotal composition on a weight basis. An amount of about 3% has givengood results and is especially preferred. All percentages given areweight-% (w/w), if not indicated otherwise.

Pharmaceutical compositions suitable for topical administration to thehands and feet, more preferably to the affected areas of the palms andsoles, are for example creams, lotions, ointments, microemulsions, fattyointments, gels, emulsion-gels, pastes, foams, tinctures, solutions,patches, bandages and transdermal therapeutic systems. Most preferredare creams or emulsion-gels.

Creams or lotions are oil-in-water emulsions. Oily bases that can beused are fatty alcohols, especially those containing from 12 to 18carbon atoms, for example lauryl, cetyl or stearyl alcohol, fatty acids,especially those containing from 10 to 18 carbon atoms, for examplepalmitic or stearic acid, fatty acid esters, e.g. glyceryltricaprilocaprate (neutral oil) or cetyl palmitate, liquid to solidwaxes, for example isopropyl myristate, wool wax or beeswax, and/orhydrocarbons, especially liquid, semi-solid or solid substances ormixtures thereof, for example petroleum jelly (petrolatum, Vaseline) orparaffin oil. Suitable emulsifiers are surface-active substances havingpredominantly hydrophilic properties, such as corresponding non-ionicemulsifiers, for example fatty acid esters of polyalcohols and/orethylene oxide adducts thereof, especially corresponding fatty acidesters with (poly)ethylene glycol, (poly)propylene glycol or sorbitol,the fatty acid moiety containing especially from 10 to 18 carbon atoms,especially partial glycerol fatty acid esters or partial fatty acidesters of polyhydroxyethylene sorbitan, such as polyglycerol fatty acidesters or polyoxyethylene sorbitan fatty acid esters (Tweens), and alsopolyoxyethylene fatty alcohol ethers or fatty acid esters, the fattyalcohol moiety containing especially from 12 to 18 carbon atoms and thefatty acid moiety especially from 10 to 18 carbon atoms, such aspolyhydroxyethyleneglycerol fatty acid ester (for example Tagat S), orcorresponding ionic emulsifiers, such as alkali metal salts of fattyalcohol sulfates, especially having from 12 to 18 carbon atoms in thefatty alcohol moiety, for example sodium lauryl sulfate, sodium cetylsulfate or sodium stearyl sulfate, which are usually used in thepresence of fatty alcohols, for example cetyl alcohol or stearylalcohol. Additives to the aqueous phase are, inter alia agents thatprevent the creams from drying out, for example humectants, such aspolyalcohols, such as glycerol, sorbitol, propylene glycol and/orpolyethylene glycols, and also preservatives, perfumes, gelling agents,etc.

Ointments are water-in-oil emulsions that contain up to 70%, butpreferably from approximately 20% to approximately 50%, water or aqueousphase. Suitable as fatty phase are especially hydrocarbons, for examplepetroleum jelly, paraffin oil and/or hard paraffins, which, in order toimprove the water-binding capacity, preferably contain suitable hydroxycompounds, such as fatty alcohols or esters thereof, for example cetylalcohol or wool wax alcohols, or wool wax or beeswax. Emulsifiers arecorresponding lipophilic substances, for example of the type indicatedabove, such as sorbitan fatty acid esters (Spans), for example sorbitanoleate and/or sorbitan isostearate. Additives to the aqueous phase are,inter alia humectants, such as polyalcohols, for example glycerol,propylene glycol, sorbitol and/or polyethylene glycol, and alsopreservatives, perfumes, etc.

Microemulsions are isotropic systems based on the following fourcomponents: water, a surfactant, for example a tensioactive, a lipid,such as a non-polar or polar oil, for example paraffin oil, natural oilssuch as olive or maize oil, and an alcohol or polyalcohol containinglipophilic groups, for example 2-octyldodecanol or ethoxylated glycerolor polyglycerol esters. If desired, other additives may be added to themicroemulsions. Microemulsions have micelles or particles with sizesbelow 200 nm and are transparent or translucid systems, the formspontaneously and are stable.

Fatty ointments are water-free and contain as base especiallyhydrocarbons, for example paraffin, petroleum jelly and/or liquidparaffins, also natural or partially synthetic fat, such as fatty acidesters of glycerol, for example coconut fatty acid triglyceride, orpreferably hardened oils, for example hydrogenated groundnut oil, castoroil or waxes, also fatty acid partial esters of glycerol, for exampleglycerol mono- and di-stearate, and also, for example, the fattyalcohols increasing the water-absorption capacity, emulsifiers and/oradditives mentioned in connection with the ointments.

With gels, a distinction is made between aqueous gels, water-free gelsand gels having a low water content, which gels consist of swellable,gel-forming materials. There are used especially transparent hydrogelsbased on inorganic or organic macromolecules. High molecular weightinorganic components having gel-forming properties are predominantlywater-containing silicates, such as aluminium silicates, for examplebentonite, magnesium aluminium silicates, for example Veegum, orcolloidal silicic acid, for example Aerosil. As high molecular weightorganic substances there are used, for example, natural, semisyntheticor synthetic macromolecules. Natural and semi-synthetic polymers arederived, for example, from polysaccharides containing a great variety ofcarbohydrate components, such as celluloses, starches, tragacanth, gumarabic and agar-agar, and gelatin, alginic acid and salts thereof, forexample sodium alginate, and derivatives thereof, such as loweralkylcelluloses, for example methyl- or ethyl-cellulose, carboxy- orhydroxy-lower alkylcelluloses, for example carboxymethyl- orhydroxyethyl-cellulose. The components of synthetic gel-formingmacromolecules are, for example, suitably substituted unsaturatedaliphatic compounds such as vinyl alcohol, vinylpyrrolidine, acrylic ormethacrylic acid.

Emulsion-gels—also called “emulgels”—represent topical compositionswhich combine the properties of a gel with those of an oil-in-wateremulsion. In contrast to gels, they contain a lipid phase which due toits fat-restoring properties enables the formulation to be massaged inwhilst, at the same time, the direct absorption into the skin isexperienced as a pleasant property. Furthermore, one can observe anincreased solubility for lipophilic active ingredients. One advantage ofemulsion-gels over oil-in-water emulsions resides in the enhancedcooling effect which is brought about by the coldness due to evaporationof the additional alcohol component, if present.

Foams are administered, for example, from pressurised containers and areliquid oil-in water emulsions in aerosol form; un-substitutedhydrocarbons. such as alkanes, for example propane and/or butane, areused as propellant. As oil phase there are used, inter aliahydrocarbons, for example paraffin oil, fatty alcohols, for examplecetyl alcohol, fatty acid esters, for example isopropyl myristate,and/or other waxes. As emulsifiers there are used, inter alia, mixturesof emulsifiers having predominantly hydrophilic properties, such aspolyoxyethylene sorbitan fatty acid esters (Tweens), and emulsifiershaving predominantly lipophilic properties, such as sorbitan fatty acidesters (Spans). The customary additives, such as preservatives, etc.,are also added.

Tinctures and solutions generally have an ethanolic base, to which watermay be added and to which there are added, inter alia, polyalcohols, forexample glycerol, glycols and/or polyethylene glycol, as humectants forreducing evaporation, and fat-restoring substances, such as fatty acidesters with low molecular weight polyethylene glycols, propylene glycolor glycerol, that is to say lipophilic substances that are soluble inthe aqueous mixture, as a replacement for the fatty substances removedfrom the skin by the ethanol, and, if necessary, other adjuncts andadditives. Suitable tinctures or solutions may also be applied in sprayform by means of suitable devices. In this case, due to the solubilityproblems of allopurinol, a salt is more appropriate for tinctures orsolutions.

Transdermal therapeutic systems with —in particular—local delivery ofallopurinol contain an effective amount allopurinol optionally togetherwith a carrier. Useful carriers comprise absorbable pharmacologicalsuitable solvents to assist passage of the active ingredient through theskin. Transdermal delivery systems are, for example, in the form of apatch comprising (a) a substrate (=backing layer or film), (b) a matrixcontaining the active ingredient, optionally carriers and optionally(but preferably) a special adhesive for attaching the system to theskin, and normally (c) a protection foil (=release liner). The matrix(b) is normally present as a mixture of all components or may consist ofseparate layers.

All these systems are well known to the person skilled in the art. Themanufacture of the topically administrable pharmaceutical preparationsis effected in a manner known per se, for example by dissolving orsuspending allopurinol in the base or, if necessary, in a portionthereof.

The compositions may also comprise conventional additives and adjuvantsfor dermatological applications, such as preservatives, especiallyparaben esters like methylparaben, ethylparaben, propylparaben,butylparaben, or quaternary ammonium compounds like benzalkoniumchloride, or formaldehyde donors like imidazonidinyl urea, or alcoholslike benzyl alcohol, phenoxyethanol or acids like benzoic acid, sorbicacid; acids or bases used as pH buffer excipients; antioxidants,especially phenolic antioxidants like hydroquinone, tocopherol andderivatives thereof, as well as flavonoids, or miscellaneousantioxidants like ascorbic acid, ascorbyl palmitate; perfumes; fillerssuch as kaolin or starch; pigments or colorants; UV-screening agents;moisturizers, especially glycerin, butylen glycol, hexylen glycol, urea,hyaluronic acid or derivatives thereof; anti-free radical agents such asvitamin E or derivatives thereof; penetration enhancers especiallypropylene glycol; ethanol; isopropanol; dimethylsulfoxide;N-methyl-2-pyrrolidone; fatty acids/alcohols such as oleic acid, oleylalcohol; terpenes such as limonen, menthol. 1-8 cineole; alkyl esterssuch as ethyl acetate, butyl acetate; ion pairing agents such assalicylic acid.

Further details concerning suitable topical formulations may be obtainedby reference to standard textbooks such as Banker and Rhodes (Ed) ModernPharmaceutics 4^(th) ed. (2002) published by Marcel Dekker Inc.; Harry'sCosmeticology (2000), 8th Edition, Chemical Publishing Co.; Remington'sPharmaceutical Sciences 20^(th) ed Mack Publishing Co. (2000).

In a preferred embodiment allopurinol is formulated as a cream,preferably in an emollient base provided the emollient base is suitablefor topical application on the skin, is substantially non-toxic andprovides a suitable carrier for allopurinol or its pharmaceuticallyacceptable salts. A properly chosen emollient base may also provide acertain amount of relief in itself. In a particular case, a moisturizingcream is preferred as a base.

Emollients may be e. g. fatty alcohols, hydrocarbons, triglycerides,waxes, esters, silicone oils and lanolin containing products. Fattyalcohols are e. g. cetyl alcohol, octyldodecanol, stearyl alcohol andoleyl alcohol. Hydrocarbons include mineral oil, petrolatum, paraffin,squalene, polybutene, polyisobuten, hydrogenated polyisobutene, cerisinand polyethylene. Triglycerides are e.g. castor oil, caprylic/caprictriglyceride, hydrogenated vegetable oil, sweet almond oil, wheat germoil, sesame oil, hydrogenated cottonseed oil, coconut oil, wheat germglycerides, avocado oil, corn oil, trilaurin, hydrogenated castor oil,shea butter, cocoa butter, soybean oil, mink oil, sunflower oil,safflower oil, macadamia nut oil, olive oil, apricot kernel oil,hazelnut oil and borage oil. Waxes include e. g. carnauba wax, beeswax,cadelilla wax paraffin, Japan wax, microcrystalline wax, jojoba oil,cetyl esters wax, and synthetic jojoba oil. Esters include e. g.isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyllinoleate, 12-15 alcohol benzoates, cetyl palmitate, myristyl myristate,myristyl lactate, cetyl acetate, propylene glycoldicaprylate/caprate,decyl oleate, stearyl heptanoate, diisostearyl malate,octylhydroxystearate and isopropyl isostearate. Silicone oils are e. g.dimethicone (dimethyl polysiloxane) and cyclomethicone. Lanolincontaining products are e. g. lanolin, lanolin oil, isopropyl lanolate,acetylated lanolin alcohol, acetylated lanolin, hydroxylated lanolin,hydrogenated lanolin and lanolin wax.

In a preferred embodiment allopurinol is prepared by mixing it with acommercial basic cream, such as Bag Balm or Basiscreme DAC (DeutschesArzneimittel codex).

The daily dosage of the topical formulation comprising allopurinol orpharmaceutically acceptable salts may depend on various factors, such assex, age, weight and individual condition of the patient, as well as thechemotherapy he is being or will be given and the severity of the HFSR.

The topical pharmaceutical compositions, e. g. in the form of creams,emulsion-gels or gels may be applied once, twice or three times daily,but also more frequent daily applications such as 5 to 10 times a dayare possible provided that the symptoms of HFSR are eliminated oravoided. The dosage may be variable, in function of the severity of theHFSR symptoms, or the cycles or dosages of the MKI therapeutictreatment. One fingertip per hand or foot per application isrecommended.

The pharmaceutical composition of the invention is administered topatients already suffering from HFSR in its different grades, or as apreventive treatment to patients susceptible to develop HFSR as aconsequence of a MKI therapeutic treatment that is administered or aboutto be administered.

The administration can be intensified shortly before, during and afterchemotherapeutic treatment, when the risks of developing HFSR arehigher, and can be reduced during periods of rest between cycles.

The invention will be further illustrated by means of examples, theyshould no be taken as limiting the scope of the invention as defined bythe claims.

EXAMPLES cl Example 1 Preparation of a Topical Formulation ComprisingAllopurinol.

-   A formulation was prepared by suspending allopurinol base (3% by    weight of total formulation) in 5% water and then adding Basiscreme    DAC (92%) and mixing.

The Composition of the Basic Cream DAC is as Follows:

-   Glycerolmonostearate: 4.0-   Cetylalcohol 6.0-   Medium chain triglyceride 7.5-   White Vaseline 25.5-   Polyoxyethylenglycerol monostearate 7.0-   Propylenglycol 10.0-   Water 40.0-   The resulting cream is distributed in suitable containers and    stored. The cream is easily applicable by the patients.

Example 2 Treatment of Hand Foot Skin Reaction

-   A male patient (65y) having developed metastatic renal cell    carcinoma (MRCC), was treated surgically and after progression of    the metastasis he was treated with Nexavar® (sorafenib) as    palliative therapy in a reduced dose (200 mg 2× daily). The therapy    was interrupted due to HFSR, fatigue, loss of appetite and diarrhea    after 7 months. A third line/second line palliative therapy was    tried with Sutent® (sunitinib), at a reduced dosage of 37.5 mg daily    for days 1-28 every 6 weeks.-   The patient had developed HFSR during the treatment with sorafenib,    with a very thick hyperkeratosis and pain to the palms and soles,    which did not disappear with the change of medication from sorafenib    to sunitinib. To try to improve his state and avoid interrupting the    cancer therapy, topical treatment was initiated with the cream    prepared in example 1, administered 3 times daily.-   Results: following the topical treatment with allopurinol, the    symptoms of HFSR disappeared nearly completely and the therapy with    sunitinib could he completed without any dose reduction or delay in    the treatment due to HFSR. No toxics effects associated to the    topical allopurinol treatment were observed.-   Surprisingly, after only one week of treatment with allopurinol, the    symptoms of HFSR reverted from grade 3 to grade 1 and 0 in most    areas. Most significantly, the thick hyperkeratosis disappeared. The    treatment with sunitinib and the allopurinol cream was continued    until interruption of the treatment because of tumor progression.

Example 3 Treatment of Hand Foot Skin Reaction

-   A male patient (74y) having developed Hepatocellular Carcinoma (HCC)    started palliative therapy with sorafenib at a initial reduced dose    (200 mg 2× daily). After 2½ months he had developed HFSR grade 1. He    was treated with the allopurinol cream as described in example 1,    and the HFSR symptoms disappeared in 7 days.-   The sorafenib dosage was escalated to the recommended dose of 400 mg    2× daily. No further HFSR symptoms were appreciated, although other    side effects such as diarrhea were present but manageable. The    patient continued his treatment with sorafenib as planned.

Example 4

-   A male patient (56y) with metastatic renal cell carcinoma (MRCC),    was diagnosed in August 2008 with bone and lung metastasis. He was    first treated with Torisel i.v. for 6 month. After progression of    the metastasis and a nephrectomy of the right kidney he was treated    with Sutent® (sunitinib) as palliative therapy in a standard dose of    50 mg daily at days 1-28 every 6 weeks.-   The patient had developed HFSR during the treatment with sunitinib,    with a keratosis (desquamation and lesions in the linger tips) and    pain to the palms and soles, which did not disappear after treatment    with emollient cream. To try to improve his state and avoid    interrupting the cancer therapy, topical treatment was initiated    with the allopurinol cream prepared in example 1, administered 3    times daily.-   Results: following the topical treatment with allopurinol, the    symptoms of HFSR nearly completely disappeared and the therapy with    sunitinib could be completed without any dose reduction or delay in    the treatment due to HFSR. No toxics effects associated to the    topical treatment with allopurinol were observed.-   After only one week of treatment with allopurinol, the symptoms of    HFSR reverted from grade 2 to grade 1 and 0 in most areas. The    treatment with sunitinib and allopurinol cream is still ongoing.

Example 5

-   A female patient (71y) first diagnosed in 2001 with renal cell    carcinoma was treated surgically. In 2005 she developed metastatic    renal cell carcinoma (MRCC) (liver and local metastasis), and after    progression of the metastasis she was treated with Nexavar®    (sorafenib) as palliative therapy (400 mg 2× daily). The therapy was    interrupted in September 2007 due to toxicity (HFSR, diarrhea). A    second line palliative therapy was tried with Sutent® (sunitinib),    at a dosage of 50 mg daily, at days 1-28 every 6 weeks. It had to be    interrupted after 1 month due to bigger toxicity problems than with    Nexavar (edema, depression, allergy), and changed back to Nexavar    (sorafenib) therapy, which after one month was complemented with the    allopurinol cream of example 1 and loperamide to treat HFSR and    diarrhea. The therapy allowed a good control of the HFSR, but not    diarrhea, for nearly two years (November 2007-September 2009). The    treatment was interrupted after cancer progression. She was then    treated during a short period of time with Afinitor (everolimus) 10    mg daily (September 2009-March 2010), which was interrupted in view    of the lack of response and tumor progression. In the absence of    alternative treatment Nexavar (sorafenib) at a reduced dosage was    resumed in March 2010. Following development of HFSR the treatment    was again complemented with the allopurinol cream one month later.-   Results: following the topical treatment with allopurinol, the    symptoms of HFSR disappeared nearly completely and the therapy with    Nexavar could be continued. No toxics effects associated to the    topical allopurinol treatment were observed.-   As shown by the examples, with the four patients that had developed    HFSR, the treatment with allopurinol improved their HFSR and allowed    the completion of MKI therapy as planned.-   Pursuant to 37 C.F.R. §1.12 c), this listing of claims will replace    all prior versions, and listings, of claims in the application:

1-10. (canceled)
 11. A method for preventing Hand Foot Skin Reaction(HFSR) induced by Multitargeted Kinase (MKI) therapy in a patient inneed thereof, comprising administering to the patient a medicamenthaving an amount of allopurinol or a pharmaceutically acceptable saltthereof which is therapeutically effective to prevent Hand Foot SkinReaction.
 12. The method according to claim 11, wherein the HFSR isinduced by sorafenib.
 13. The method according to claim 11, wherein theHFSR is induced by sunitinib.
 14. The method according to claim 11,wherein the medicament is administered topically to the skin.
 15. Themethod according to claim 14, wherein the medicament is administeredtopically to the skin of the hands or feet.
 16. The method according toclaim 11, wherein the medicament is a cream.
 17. The method according toclaim 16, wherein the medicament is a hydrophilic cream.
 18. The methodaccording to claim 11, wherein the medicament comprises from about 1% toabout 10% by weight of the composition of allopurinol or apharmaceutically acceptable salt thereof.
 19. The method according toclaim 18, wherein the medicament comprises from about 1% to about 5% byweight of the composition of allopurinol or a pharmaceuticallyacceptable salt thereof.
 20. The method according to claim 19, whereinthe medicament comprises about 3% by weight of the composition ofallopurinol or a pharmaceutically acceptable salt thereof.
 21. Themethod according to claim 12, wherein the medicament is administeredtopically to the skin of the hands or feet.
 22. The method according toclaim 13, wherein the medicament is administered topically to the skinof the hands or feet.
 23. The method according to claim 12, wherein themedicament comprises from about 1% to about 10% by weight of thecomposition of allopurinol or a pharmaceutically acceptable saltthereof.
 24. The method according to claim 13, wherein the medicamentcomprises from about 1% to about 10% by weight of the composition ofallopurinol or a pharmaceutically acceptable salt thereof.
 25. Themethod according to claim 15, wherein the medicament comprises fromabout 1% to about 10% by weight of the composition of allopurinol or apharmaceutically acceptable salt thereof.
 26. The method according toclaim 25, wherein the medicament comprises from about 1% to about 5% byweight of the composition of allopurinol or a pharmaceuticallyacceptable salt thereof.
 27. The method according to claim 26, whereinthe medicament comprises about 3% by weight of the composition ofallopurinol or a pharmaceutically acceptable salt thereof.
 28. Themethod according to claim 23, wherein the medicament comprises fromabout 1% to about 5% by weight of the composition of allopurinol or apharmaceutically acceptable salt thereof.
 29. The method according toclaim 24, wherein the medicament comprises from about 1% to about 5% byweight of the composition of allopurinol or a pharmaceuticallyacceptable salt thereof.